Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates to new and useful 1,4-dihydropyridine derivatives promoting the activity of some antitumor agents against various kinds of tumor cells including multiple drug resistant cells and also to their use, and further, to processes for the preparation of the novel derivatives.
• this invention relates to new 2,6-dimethyl-4-(pyrazolc[1,5-a]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives of the formula (I) and their hydrates and salts, wherein R is a lower and their hydrates and salts, wherein R 1 is a lower alkyl group, R 2 is a hydrogen atom, halogen atom, lower alkoxy, or a nitro group, and R and R 3 are each independently alkyl, lower alkoxyalkyl, aralkyl group or (A is straight.
• R 4 and R 5 are each independently a hydrogen atom, lower alkyl, aralkyl group or connected with each other to make five- or six-membered heterocycles which may contain other hetero atoms, to processes for their preparation and to their use in cancer chemotherapy.
• alkyl group as it is employed herein includes a straight or branched chain containing 1 to 10 carbon atoms, e.g. a methyl, isopropyl,or octyl group.
• lower alkyl group includes a straight or branched chain containing between 1 and 6 carbon atoms, e.g. a methyl, ethyl or isopropyl group.
• aralkyl group includes a lower alkyl group which is substituted by an aryl group, e.g. benzyl or phenethyl.
• lower alkoxyalkyl group includes an alkyl group which is substituted by a straight or branched chain containing 1 to 6 carbon atoms, e.g. a methoxymethyl or methoxyethyl group.
• straight or branched alkylene group includes, e.g. an ethylene or 2-methylpropylene group.
• five- or six-membered heterocycle which may contain other hetero atomsincludes, e.g. piperazine, pyrrolidine,piperidine, morpholine or thiomorpholine.
• halogen atom includes e.g. fluorine, chlorine and bromine.
• the tumor cells resistant to one of the antitumor agents show cross-resistance to the other antitumor agents (Multiple Drug Resistance : MDR), and overcoming this type of resistance is more difficult in the clinical cancer chemotherapy.
• MDR Multiple Drug Resistance
• Intracellular calcium ions are the chemical mediator which carries on the physiological function in some particular tissues, that is, plays an important rcle in the excitation-contraction coupling of heart muscle and also in the excitation-contraction coupling of vascular smooth muscle. Intracellular distribution and transport of calcium ion play a key role in their physiological function. The pharmacological action of various calcium antagonists is induced as a consequence of inhibition of calcium influx or function.
• this type of combination treatment may have therapeutic efficacy not only at the late stage when tumor acquired resistance, but also at the initial stage of chemotherapy.
• R 1 is lower alkyl group
• R 2 is a hydrogen atom, halogen atom, lower alkyl, lower alkoxy, or nitro group
• R and R 3 are each independently alkyl, lower alkoxyalkyl, aralkyl group, or -A- (A is straight or branched alkylene group
• R and R are each independently a hydrogen atom, lower alkyl, aralkyl group, or connected with each other to make five- or six-membered heterocycles which may contain other hetero atom).
• the compounds of the formula (I) can be converted, if desired, to pharmaceutically acceptable acid salts by the treatment with acid wherein either of R and R 3 are a -A- group.
• the acid may be an organic or inorganic acid such as, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, oxalic acid, fumaric acid or lactic acid.
• the compound of the formula (I), hydrates and salts thereof may be used as medicine in the conventional form of pharmaceutical preparations, which may be, for example, tablets, capsules, powder, ointment, suppositories, syrup, liquor, suspension, spray or injection, suitable for peroral, parenteral, enteral or local administration.
• the resulting hydrochloric acid layer was alkalized with 5 N-aqueous sodium hydroxide at pH 9, and then extracted with ethyl acetate.
• the ethyl acetate layer was washed with salt water, dried over anhydrous sodium sulfate and then concentrated. Hexane was added to the resulting residue, and insoluble layer was collected, then recrystallized from diethyl ether-hexane mixtures.
• the derivatives of this invention promoted the activity of antitumor agents, and the potency was equal to those of verapamil and nifedipine in vitro culture of P388/VCR and P388/ADR cells.
• the derivatives showed low values (pA 10 : 5.6-6.1) of calcium antagonizing activity as compared with values of verapamil (pA lO : 7.5) and nifedipine (pA 10 : 8.8) by assessing the dose-dependent relaxing effect using the Magnus's method with isolated preparation of guinea-pig caecum strip.
• VCR 0.1 mg/kg
• Example 6 or verapamil at doses indicated in Table 2
• sterile physiological saline were administered twice a day (in the morning and evening) intraperitoneally for 5 consecutive days.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (2)

Publications (3)

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ID=17634240

Family Applications (1)

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Cited By (9)

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• 1986
  • 1986-11-26 JP JP61281093A patent/JPS63135381A/ja active Pending
• 1987
  • 1987-11-17 CA CA000552010A patent/CA1309717C/fr not_active Expired - Lifetime
  • 1987-11-18 AU AU81356/87A patent/AU605518B2/en not_active Ceased
  • 1987-11-25 US US07/125,373 patent/US4923871A/en not_active Expired - Fee Related
  • 1987-11-25 EP EP87117394A patent/EP0270926B1/fr not_active Expired - Lifetime
  • 1987-11-25 DE DE8787117394T patent/DE3784865D1/de not_active Expired - Lifetime
  • 1987-11-25 HU HU875304A patent/HU198930B/hu unknown
  • 1987-11-25 CN CN87101183A patent/CN1016783B/zh not_active Expired
  • 1987-11-26 KR KR870013372A patent/KR880006238A/ko not_active Ceased

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